3-substituted-6-lower-alkyl-10-methyl-2h, 8h-pyrano[3,2-g]-4, 4-benzoxazine-2, 8 diones



United States Patent 3-SUBSTITUTED-6-LOWER-ALKYL-10-METHYL-2H, 8H-PYRANO[3,2-g]-4,4-BENZOXAZINE-2,8 DIONES Robert B. Mofiett, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Dec. 3, 1963, Ser. No. 327,801

4 Claims. (Cl. 260-244) It Formula I wherein R is a member selected from the group consisting of lower-alkyl, phenyl, and

R is lower-alkyl; X is lower-alky; and n is an integer from 1 to 7, inclusive.

As used in the present specification and claims the term lower-alkyl is used to mean an alkyl group of from 1 to 8 carbon atoms inclusive, for example, methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl and octyl and the isomeric forms thereof.

The novel compounds of the invention are prepared by condensing a 4-lower-alkyl-6-amino-7-hydroxy-8- methylcoumarin with an a-keto ester according to the following equation:

-O Compound 01 Formula I O o i wherein R, R and X are as defined above.

The condensation is accelerated by gentle heating (from room temperature, about 25 C., to about 180 C., the optimum temperature depending upon the nature of the R moiety) and advantageously is carried out in a non-oxidizing atmosphere, for example, nitrogen. The proportions of reactants can be varied over a wide range. Equimola-r amounts are suitable though sometimes it is desirable to use an excess of one or the other reactant, say up to about 100 percent excess. An inert solvent, for example, toluene, ethanol, dioxane or tetrahydrofuran, can be used if desired or an excess of the u-keto ester, when it is liquid, can serve as inert solvent.

The novel compounds of the invention have tranquilizing and analgetic activity and can be used to calm agitated mammals or animals, e.g., laboratory rats and mice. For example, 3,6,l0-trimethyl-2H,8H-pyrano[3,2-g]-1,4- benzoxazine-2,8-dione gives over 60 percent reduction of motor activity in mice when parenterally administered at doses as low as 10 percent of the LD The LD in mice is l000 mg./kg.

The compounds of the invention are also useful for light filters, giving strong absorption bands in the vicinity of 213, 24, 302 and 362 millimicrons. For this purpose "ice they can be used in solutions, suspensions, ointments, or they can be dispersed in plastic films.

The invention can be more fully understood by reference to the following examples which are given by way of illustration and not of limitation. Parts and percentages are by weight unless otherwise specified.

EXAMPLE 1.3 ,6,10-TRIMETHYL-ZH-SH-PYRANO [3,2-g] -l ,4-BENZOXAZINE-2,8-DIONE A slurry of 10.3 gm. (0.05 mole) of 6-amino-7-hydroxy-4,8-dimethylcoumarin [R. B. Moflett, J. Med. Pharm. Chem. 5,335 (1962)] in 25 gm. of ethyl pyruvate was heated under nitrogen in an oil bath at l30145 C. for 1 hour. The product was boiled with 100 ml. of ethanol and cooled, giving 6.25 gm. of yellow-brown solid, M.P. 226-235 C. (dec.). The solid was recrystallized from ml. of n-butanol, giving 3.9 gm. of yellow solid, M.P. 234 C. (dec.). The yellow solid was dissolved in benzene, filtered, concentrated to dryness, and the solid residue was recrystallized from 15 ml. of dimethylformamide, giving 1.74 gm. of olive colored crystals of 3,6,10-trimethyl-2H,8H-pyrano[3,2-g]-1,4- benzoxazine-2,8-dione having a melting point of 253 256 C. (dec.). Infrared and ultraviolet spectra were in agreement with the proposed structure.

AnaL-Calcd. for C H NO C, 65.36; H, 4.31; N, 5.45. Found: C, 65.04; H, 4.72; N, 5.54.

EXAMPLE 2.-3,6,l0-TRlMETHYL-2H,8H-PYRANO [3 ,2-g] -1,4-BENZOXAZINE-2,8-DIONE A mixture of 20.6 gm. (0.1 mole) of 6-amino-7-hydroxy-4,8-dimethylcoumarin and 20.4 gm. (0.2 mole) of methyl pyruvate was allowed to stand at room temperature under nitrogen for /2 hour. It became more fluid and then set solid. After warming on a steam bath for 1 hour the mixture was boiled with 85 ml. of ethanol and cooled. The solid was collected and dried, giving 23.8 gm. (96%) of bright yellow 3,6,l0-trimethyl-2H-8H- pyrano[3,2-g]-l,4-benzoxazine-2,8-dione having a melting point of 260-264 C. A mixed melting point with the product of Example 1 showed no depression.

U.V.' spectrum in EtOH max.: 5

Following the foregoing procedure, in place of 6- amino-7-hydroxy-4,S-dimethylcoumarin there can be substituted an equimolar amount each of 4-ethyl-6-amino-7- hydroxy-8-methylcoumarin, 4-propyl-6-amino-7-hydroxy- S-methylcoumarin, 4-butyl-6-amino-7-hydroxy-8-rnethylcoumarin, 4-amyl-6-amino-7-hydroxy-8-methylcoumarin, and 4 octyl 6 amino-7-hydroxy-8-methylcoumarin. There can thus be obtained the corresponding 6-alkyl- 3,10 dimethyl 2H,8H-pyrano[3,2-g]-1,4-benzoxazine- 2,8-diones.

EXAMPLE 3 .6, l 0-DIMETHYL-3 -PHENYL-2H,8H- PYRANO [3,2-g] -1,4-BENZOXAZINE-2,8-DIONE 3 yl 3-phenyl-2H,8H-pyrano[3,2-g]-1,4-benzoxazine2,8- dione having a melting point of 255-256 C. The infrared and ultraviolet spectra were in accordance with the proposed structure.

Anal.-Calcd. for C H NO C, 71.47; H, 4.10; N, 4.39. Found: C, 71.21; H, 4.07; N, 4.34.

Following the foregoing procedure, in place of ethyl phenylglyoxylate there can be substituted an equilmolar amount each of methyl ethylglyoxylate, methyl propylglyoxylate, methyl amylglyoxylate, and methl octylglyoxylate. There can thus be obtained the corresponding 3 alkyl 6,10 dimethyl-2H,8H-pyrano[3.2-g]-1,4-benzoxazine-2,8-diones.

EXAMPLE 4.3-CARBETHOXYMETHYL-6,IO-DI- METHYL 2H,8H PYRANO[3,2-g] 1,4-BENZOX- AZINE-LS-DIONE A mixture of 20.6 gm. (0.1 mole) of 6-amino-7-hydroxy-4,8-dimethylcoumarin and 33.6 gm. (0.18 mole) of diethyl oxal-acetate was allowed to stand at room temperature under nitrogen for 2 hours. It became fluid (but did not all dissolve) and then set solid. After warming on a steam bath for 1 hour, the mixture was boiled with ethanol, cooled, and filtered, giving 31 gm. of yellow solid, M.P. 231235 C. This was recrystallized from dimethylformamide, giving 24.6 gm. (75%) of 3-carbethoxyrnethyl-6, 1 -dimethyl-2H,8H-pyrano 3,2- g]-1,4-benzoxazine-2,8-dione as a yellow solid, M.P. 240- 242.5 C.

AnaL-Calcd. fOl' C17H15NOI C, H, N, 4.25; O, 29.15. Found: C, 62.07; H, 4.55; N, 4.60; O, 28.97.

UV. spectrum in EtOH 7\ max.: 6

Following the foregoing procedure, in place of diethyl oxalacetate there can be substituted an equimolar amount of other di-lower-alkyl esters of oxalacetic acid, e.g., the methyl, propyl, isopropyl, butyl, sec-butyl, amyl, isoamyl, heptyl, Z-ethylhexyl, and octyl esters to give the correwherein R is a member selected from the group consisting of lower-alkyl, phenyl and R is lower-alkyl; X is lower-alkyl; and n is an integer from 1 to 7, inclusive.

2. 3,6,10 trimethyl 2H,8H-pyrano[3,2-g]-1,4-benzoxazine-2,8-dione.

3. 6,10 dimethyl 3-phenyl-2H,8H-pyrano[3,2-g]- l ,4-benzoxazine-2,8-dione.

4. 3 carbethoxymethyl-6,10-dimethy1-2H,8H-pyran0 [3,2-g]-l,4-benzoxazine-2,8-dione.

References Cited by the Examiner UNITED STATES PATENTS 3,105,071 9/1963 Motfett 260-244 FOREIGN PATENTS 815,279 6/ 1959 Great Britain.

WALTER A. MODANCE, Primary Examiner.

R. T. BOND, Assistant Examiner. 

1. A COMPOUND OF THE FORMULA 